Cytosolic ROS Formation Promoted by Metabolic Stress-induced Iron Transport Causes Secondary Beta-Cell Mitochondrial Dysfunction and Apoptosis

Metabolic stress has been proposed to induce β cell-damage by iron-catalyzed formation of reactive oxygen species (ROS). We have shown that inducible β cell-specific knock-out (KO) of divalent metal transporter 1(DMT1) protects against high-fat diet (HFD) induced diabetes (Cell Metab 2012), but the molecular mechanisms are unknown. Here we show that glucolipotoxic conditions (GLT) doubled DMT1 and transferrin receptor, but not ferritin heavy/light chain, ferroportin, pancreatic duodenum homeobox 1 or insulin 1 mRNA expression in MIN6 cells, correlating with a two-fold increase in the the labile iron pool (LIP) in MIN6 cells, mouse and human islets, and in islets from mice with HFD induced obesity. Iron chelation reduced LIP, apoptosis, cytosolic ROS, IL-6 and monocyte chemotactic factor expression in GLT-exposed mouse islets, and alleviated FFA-mediated inhibition in glucose- and KCl-induced mouse and human islet insulin secretion. DMT-1 KO prevented GLT induced increases in islet LIP, ROS and apoptosis, associated with improved mitochondrial membrane potential, and alleviated GLT induced inhibition of insulin secretion from perifused DMT-1KO islets. This study identifies a novel pathway underlying metabolic stress-induced apoptosis involving increased iron import and ROS formation in the cytosolic compartment causing dissipation of the mitochondrial membrane potential. We conclude that iron transport via DMT-1 is a novel central mechanism relaying metabolic stress with ROS production, cell dysfunction and death. Taken together with the accumulating epidemiological evidence suggesting that iron overload leads to diabetes and that patients with diabetes have increased tissue iron accumulation, our findings highlight control of iron levels as an attractive novel treatment option for the prevention of diabetes. Clinical trials are warranted to validate this translation of our preclinical findings